MXPA01007012A - Analgesic compositions comprising anti-epileptic compounds and methods of using same - Google Patents

Abstract

The present invention is directed to novel combinations of one or more anti-epileptic compounds that demonstrate pain alleviating properties, with one or more compounds selected from the group consisting of analgesics, NMDA receptor antagonists, NSAIDs, and combinations thereof, and pharmaceutical compositions comprising same. It has been discovered that the administration of anti-epileptic compounds that demostrates pain alleviating properties in these novel combinations results in an improved reduction in the frequency and severity of pain. It is also believed that the incidence of unwanted side effects can be reduced by these novel combinations in comparison to using higher doses of a single agent treatment to achieve a similar therapeutic effect. The present invention is also directed to methods of using effective amounts of the novel pharmaceutical compositions to treat pain in mammals.

Description

ANALGESIC COMPOSITIONS THAT COMPRISE ANTI-EPILEPTIC COMPOUNDS AND METHODS OF USE THEREOF FIELD OF THE INVENTION The present invention is directed to novel combinations of antiepileptic compounds that demonstrate pain-relieving properties, with compounds selected from the group consisting of analgesics, N-methyl-D-aspartate (NMDA) receptor antagonists and anti-retroviral drugs. Non-steroidal inflammatories (NSAIDs) and pharmaceutical compositions comprising the same. It has been found that the administration of anti-epileptic compounds demonstrating pain relief properties in these novel combinations results in an improved reduction in the frequency and severity of pain. It is believed that the incidence of unwanted effects can be reduced by novel combinations compared to the use of high doses of a single agent treatment to achieve a similar therapeutic effect. The present invention is also directed to methods of using effective amounts of novel pharmaceutical compositions for treating pain in mammals.

BACKGROUND OF THE INVENTION A number of treatments involving the administration of simple drugs are currently recommended for pain relief. The administration alone of narcotics and non-narcotic analgesics and NSAIDs have shown that they display properties for pain relief. Some anti-epileptics, such as gabapentin and pregabalin have also shown pain relief properties. Despite the benefits derived from current regimens of pain relief with only the drug, these regimens have disadvantages. One area of concern is related to the incidence of side effects denounced by many of the pain management regimens available today. Narcotic analgesics, such as morphine, are scarcely prescribed for pain because their addictive effects and significant side effects on the central nervous system (CNS) and the gastrointestinal side effects resulting from their administration are well known. Another class of drugs commonly used alone for the treatment of pain, non-steroidal anti-inflammatory drugs, such as ibuprofen and naproxen, are criticized for their irritation of the gastrointestinal tract. Another concern of current regimens for the treatment of pain related to their effectiveness. Many individual active ingredients in current regimens for pain relief can not achieve adequate pain relief even at their maximum approved therapeutic doses in some severe pain states. In addition to not achieving adequate pain relief, increasing the dose of the drug can produce an increase in unwanted side effects such as cognitive deterioration, nausea and constipation. In view of these concerns, it is clear that there is a need for an improved pain regimen that provides a therapeutic benefit (i.e., reduces the severity and / or frequency of pain) and / or reduces the incidence of unwanted side effects caused by many current regimes.

SUMMARY OF THE INVENTION It has now been surprisingly found that anti-epileptic compounds having pain-relieving properties when co-administered with compounds selected from the group consisting of analgesics, NMDA receptor antagonists and NSAIDs results in unexpectedly improved pain relief. . The present invention is directed to novel combinations for pain relief, combinations comprising anti-epileptic compounds, such as gabapentin and pregabalin, which have displayed pain relief properties and compounds selected from the group consisting of NMDA receptor antagonists, analgesics and NSAIDs. It is also believed that the incidence of undesired side effects can be reduced by co-administering these compounds with anti-epileptic compounds that have pain relief properties compared to the use of high doses of a single agent treatment to achieve a similar therapeutic effect. The present invention is also directed to pharmaceutical compositions comprising novel combinations of certain anti-epileptic compounds with compounds selected from the group consisting of NMDA receptor antagonists., analgesics and NSAIDs. The active ingredients are combined with at least one pharmaceutically acceptable carrier. The pharmaceutical compositions are prepared in a wide variety of pharmaceutical delivery systems known to those skilled in the art, preferably parenteral and oral dosage forms. The present invention is also directed to methods for the treatment of mammals suffering from pain with the novel pharmaceutical composition for pain relief. The method comprises the step of administering the pharmaceutical compositions comprising anti-epileptic combinations for mammals in need of such pain relief.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows the anti-hyperalgesic actions of the fixed combinations 1: 1 (1 part by weight of gabapentin to 1 part of naproxen sodium) of gabapentin and naproxen sodium in various doses, where: A = Dosage (mg / kg / ig). B = Latency of the fast movement in the leg. (a) Mixture of gabapentin-naproxen. (b) Gabapentin in 120 min. (c) Naproxen in 120 min. (d) Additive line (1: 1) Figure 2 shows the anti-hyperalgesic actions of the fixed combinations 50: 1 (50 parts by weight of gabapentin for 1 part by weight of naproxen sodium) of gabapentin and naproxen sodium in various doses , where: (e) Gabapentin-naproxen mixture (1: 1) (b) Gabapentin in 120 min. (c) Naproxen in 120 min. (f) Additive line-technical dose.

DETAILED DESCRIPTION OF THE INVENTION It has unexpectedly been found in accordance with the present invention that the analgesic effects can be improved by the co-administration of one or more anti-epileptic compounds demonstrating pain relief properties together with one or more components selected from the group consisting of analgesics, NSAIDs, NMDA receptor antagonists and combinations thereof. As used herein, the term "co-administration" means including the administration of the anti-epileptic compounds before, during or after administration of compounds selected from the group consisting of NMDA receptor antagonists, analgesics and NSAIDs. An advantage of using the novel combinations described herein is the reduced severity and / or frequency of pain. Another potential advantage is the complete improvement in pain control, which may include a reduction in dose and unwanted side effects.

The analgesics used in this invention can be, for example, non-narcotic analgesics or narcotic analgesic compounds. Non-narcotic analgesics are generally defined as those compounds that relieve pain without being addictive. A non-limiting example of a non-narcotic analgesic includes acetaminophen. Narcotic analgesics are generally defined as those compounds that are addictive when administered to treat pain in a mammal. Non-limiting examples of non-narcotic analgesics include opiates, opiate derivatives, opioids and their pharmaceutically acceptable salts. Specific non-limiting examples of narcotic analgesics include alfentanil, alphaprodine, anileridine, bezitramide, codeine, dihydrocodeine, diphenoxylate, ethylmorphine, fentanyl, heroin, hydrocodone, hydromorphone, isomethadone, levomethorphan, morphine, neperidine, oxycodone, fenomorphan, phenoperidine, piritradide, pholcodine, proheptazoine, propian, reacemoramide, tebacon, trimeperidine and the pharmaceutically salts thereof. The term "N-methyl-D-aspartate receptor" should be understood to include all subcategories of the binding site associated with the NMDA receptor, ie, the glycine binding site, the binding site (PCP), phencyclidine, etc., as well as the NMDA channel. The invention, in this document contemplates the use of non-toxic substances that block or interfere with the NMDA receptor binding site. In a preferred embodiment NMDA receptor antagonists that can be used in novel combinations are compounds that block or reduce the effects of NMDA in the NMDA subclass of neuronal glutamate receptors (non-limiting examples include dextrorphan, dextromethorphan and cetamide) or blocking or interfere with the NMDA channel (ie, a substance that blocks magnesium or the calcium channel). In a preferred embodiment, the NMDA receptor antagonist is one that is specific for a subtype of the NMDA receptor, those containing the NR2B subunit that are expressed in the brain (non-limiting examples include (1S, 2S) -1- (4- hydroxyphenyl) 2- (4-hydroxy-4-phenylpiperidine) -1-propanol). Other NMDA receptor antagonists act at other sites of an NMDA receptor that include but are not limited to GV-150526 (a compound in pre-clinical development by GlaxoWeIlcome), ifenprodil and ACEAs 1168. The term "NSAID" is used to describe other compounds useful in the novel combination of this document, it is intended that it be a non-steroidal anti-inflammatory compound. NSAIDs are characterized by their ability to inhibit cyclooxygenase. Cyclooxygenase 1 and cyclooxygenase 2 are the two main isoforms of cyclooxygenase and the most standard NSAIDs are mixed inhibitors of two isoforms. The most standard NSAIDs fall into the following five structural subcategories: (1) propionic acid derivatives, such as ibuprofen, naproxen, naprosin, diclofenac and ketoprofen; (2) acetic acid derivatives, such as tolmetin and sulindac; (3) fenamic acid derivatives, such as mefenamic acid and meclofenamic acid; (4) biphenylcarboxylic acid derivatives, such as diflunisal and flufenisal and (5) oxicams, such as piroxim, sudoxicam and isoxican. Other useful NSAIDs include aspirin. Another class of NSAIDs have been recently described that selectively inhibit cyclooxygenase 2. These compounds reduce pain and inhibit the inflammatory response without damaging the gastric mucosa, a common toxicity observed with mixed inhibitors. (Z) -5 - [[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -2-imino-4-thiazolidinone methanesulfonate (1: 1), celecoxib, meloxicam and their pharmaceutically acceptable salts are examples of selective cyclo-oxygenase-2 inhibitors. The term "anti-epileptic compound" is generally defined as a pharmaceutically acceptable active ingredient that treats disorders characterized by recurrent attacks of psychic malfunctions, sensors and motors with or without convulsive movements or unconsciousness. Non-limiting examples of the anti-epileptic compounds having analgesic activity include gabapentin, pregabalin, carbamazepine, lamotrigine, phenytoin, fosphenytoin and analogues thereof. The term "pain relief properties" generally defined in this document includes the terms "repressing pain", "reducing pain" and "inhibiting pain" as the invention is applicable to alleviate existing pain as well as the suppression or inhibition of pain that could otherwise continue from the event causing the eminent pain. In a preferred embodiment of the present invention, antiepileptic compounds having pain relief properties include those having the following formula I: wherein R- \ is hydrogen or a lower alkyl, n is an integer from 4 to 6 and the cyclic ring is optionally substituted and the pharmaceutically acceptable salts thereof. The term "lower alkyl" includes the long-chain or branched alkyl groups of more than eight carbon atoms. An especially preferred embodiment uses a compound of Formula I wherein R. is hydrogen and n is 5, which compound is 1- (aminomethyl) -cyclohexane acetic acid, generically known as gabapentin. Other preferred compounds of the above Formula I include, but are not limited to, 1-aminomethyl-1-cyclohexane-ethyl acetate, 1-aminomethyl-1-cycloheptane-acetic acid, 1-aminomethyl-1-cyclopentane-acetic acid. , methyl-1-aminomethyl-1-cyclohexane-acetate, 1-aminomethyl-1-cyclohexane-n-butyl acetate, 1-aminomethyl-1-cycloheptane-methyl acetate, 1-aminomethyl-1-cycloheptane-n-acetate -butyl. toluene sulfonate, 1-aminomethyl-1-cyclopentane-acetate, benzene-sulfonate and 1-aminomethyl-1-cyclopentane-n-butyl acetate. Other preferred compounds of Formula I above, wherein the cyclic ring is substituted for example with alkyl such as methyl or ethyl, include, but are not limited to (1-aminomethyl-3-methylcyclohexyl) -acetic acid, (1-) aminomethyl-3-methylcyclopentyl) acetic acid and (1-aminomethyl-3,4-dimethylcyclopentyl) -acetic acid. In another preferred embodiment of the present invention, antiepileptic compounds that have pain relieving properties include those that are included in Formula II: wherein Rn is a long or branched chain alkyl of 1 to 6 carbon atoms, phenyl or cycloalkyl having from 3 to 6 carbon atoms; R.2 is hydrogen or methyl and R. is hydrogen, methyl or carboxyl or an enantiomeric or diastereomeric isomer thereof or a pharmaceutically acceptable salt thereof. The most preferred compound of Formula II is where R 2 and R 3 are both hydrogen and R 1. is - (CH2) 0-2-iC4H9 as an (R), (S) or isomer (R, S). A more preferred embodiment of the invention uses 3-aminoimethyl-5-methyl-hexanoic acid and especially (S) -3- (aminomethyl) -5-methylhexanoic acid, currently generically as pregabalin. Another preferred compound is 3- (1-aminoethyl) -5-methylhexanoic acid. In the preferred embodiment of the present invention, the combination will be comprised of the compounds of Formula I in combination with one or more compounds of Formula I in combination with one or more compounds selected from the group consisting of NSAIDs, analgesics, receptor antagonists. NMDA and combinations thereof. In a more preferred embodiment of the present invention, the combination will contain the compound, gabapentin, as the anti-epileptic drug in combination with one or more compounds selected from the group consisting of NSAIDs, analgesics, NMDA receptor antagonists and combinations thereof. . In one embodiment of the present invention, an individual anti-epileptic compound is combined with a single compound selected from the group consisting of NSAIDs, analgesics and NMDA receptor antagonists. While any anti-epileptic compound described herein can be combined with any NSAID, analgesic, or NMDA receptor antagonist described herein, the preferred anti-epileptic compound is gabapentin. Preferred combinations include, but are not limited to, gabapentin / opioid, gabapentin / morphine, gabapentin / hydrocodone, gabapentin / oxycodone, gabapentin / ibuprofen, gabapentin / naproxen, gabapentin / acetaminophen, pregabalin / opioid, pregabalin / morphine, pregabalin / hydrocodone , pregabalin / oxycodone, pregabalin / ibuprofen, pregabalin / naproxen and pregabalin / acetaminophen. In another embodiment of the present invention, a single anti-epileptic compound is combined with two or more, preferably two, compounds selected from the group consisting of NSAIDs, analgesics, NMDA receptor antagonists or combinations thereof. While any anti-epileptic compound described in this document can be combined with any of the two compounds selected from NSAIDs, analgesics, NMDA receptor antagonists or combinations thereof, the preferred antiepileptic compound is gabapentin. Preferred combinations include but are not limited to gabapentin / morphine / naproxen, gabapentin / opioid / NSAID, gabapentin / morphine / ibuprofen, gabapentin / hydrocodone / acetaminophen, gabapentin / oxycodone / acetaminophen, pregabalin / morphine / naproxen, pregabalin / opiode / NSAID , pregabalin / morphine / ibuprofen; pregabalin / hydrocodone / acetaminophen, pregabalin / oxycodone / acetaminophen. In another embodiment of the present invention, two or more antiepileptic compounds are combined with one or more compounds selected from the group consisting of NSAIDs, analgesics, NMDA receptor antagonists or combinations thereof. While the anti-epileptic compounds described herein may be combined with one or more compounds selected from NSAIDs, analgesics, NMDA receptor antagonists or combinations thereof, preferred antiepileptic compounds are selected from the compounds of Formulas I and II. Preferred combinations include, but are not limited to, gabapentin / pregabalin / opioid, gabapentin / pregabalin / NSAID, gabapentin / pregabalin / naproxen. In addition to its pain-relieving properties, gabapentin is extremely well tolerated and has been shown to be virtually free of drug interactions. The unique properties and mechanism of action of anti-epileptic compounds such as gabapentin, which demonstrate properties for pain relief, could be used in the combinations described above with the benefit of providing better pain relief than if they were used without combination. An added benefit to using the combination would be to use reduced amounts of medication, in order to potentially reduce adverse events for the patient. The amount of the active ingredients in the combinations will vary depending on the mammal to which the combinations are administered, the type of pain to be treated, other active ingredients present, etc. Generally, the amount of the antiepileptic compounds and the other active compounds for a given composition and dosage form can be quickly determined using routine procedures.

The present invention is also directed to methods of treating mammals for pain relief by co-administering one or more anti-epileptic compounds having pain relief properties and one or more compounds selected from the group consisting of analgesics, NSAIDS , NMDA receptor antagonists and combinations thereof. Any of the combinations described in this document can be used for the treatment. The types of treatable pain suffered by mammals are varied and known to doctors. Non-limiting examples of pain in mammals include centrally mediated pain, peripherally mediated pain, pain related to soft or structural tissue damage, pain related to progressive disease (ie, oncology) and neuropathic pain states, which will include conditions of acute pain (ie, acute injury or trauma, pre and post-surgical, headache such as a migraine), chronic (ie, neuropathic pain conditions such as diabetic peripheral neuropathy and post-hepatic neuralgia) and conditions of pain due to inflammatory condition (ie, rheumatoid arthritis or osteoarthritis, sequelae due to acute injury or trauma). The pharmaceutical compositions containing the combinations of the present invention or their salts are produced by formulating the active compounds in the unit dosage form with a pharmaceutical carrier. Examples of suitable unit dosage forms are tablets, capsules, pills, powders, aqueous and non-aqueous oral solutions and suspensions and parenteral solutions packaged in containers containing one or more large numbers of dose units and capable of being subdivided into individual doses. . Some examples of suitable pharmaceutical carriers, including pharmaceutical diluents, are gelatin capsules; sugars such as lactose and sucrose; starches such as corn starch and potato starch; cellulose derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose and cellulose acetate phthalate; jelly; talcum powder; stearic acid; magnesium stearate, vegetable oils such as peanut oil, safflower oil, sesame oil, olive oil, corn oil and theobroma oil; propylene glycol; propylene glycol, glycerin, sorbitol; polyethylene glycol; water, agar, alginic acid, isotonic saline and phosphate stabilizing solutions; as well as other compatible substances normally used in pharmaceutical formulations. The compositions of the invention may also contain other components such as coloring agents, flavoring agents and / or preservatives. These materials, if present, are usually used in relatively small amounts. The compositions, if desired, may also contain suitable pharmacologically active components. Preferred routes of administration of the subject combinations are oral or parenteral. The doses will vary depending on the mammal and a number of other factors.

EXAMPLES Example 1 The objective of this experiment was to characterize the antinociceptive and antiinflammatory effects of gabapentin administered in combination with a prototypical NSAID in the rat. In this example, gabapentin, naproxen sodium and the combination of gabapentin and naproxen sodium were evaluated in a thermal hyperalgesia test of the carrageenan retention cushion in standard rats. This test uses an extract of seaweed (carrageenan) which, when injected into the retention cushion for the test animals, caused a sterile inflammation, thus decreasing the pain threshold. Anti-epileptic agents that have analgesic properties, such as gabapentin, raise the pain threshold to become normal, thus facilitating the animal tolerating an external source of pain for a long period of time relative to untreated control animals. .

As shown in Figure 1, gabapentin and naproxen sodium were provided alone (gabapentin in 120 min after dosing, naproxen sodium in 120 min after dosing). Each data point represents the mean and the standard error of the mean. The data for each drug were adjusted by at least linear regression of squares for a straight line. The theoretical dose-additive line for a 1: 1 ratio was determined (dotted line) as described. (Tallarida, 1992). The experimental determination of a 1: 1 dose ratio was determined (gabapentin-sodium naproxen 1: 1 mixture) and found to be significantly different from the theoretical dose-additive line. Therefore, a supra-additive effect was determined by the combination of two treatments given simultaneously. As shown in Figure 2, the experiment was performed as described in Figure 1 and similarly a supra-additive effect was determined for the combination of two treatments given simultaneously, except that the theoretical dose-additive line (dotted line) and experimental data (open boxes) were determined for a 50: 1 ratio of a dose of gabapentin for a dose of naproxen sodium. To summarize, the data showed that both gabapentin (3-100 mg / kg PO) and naproxen sodium (0.3-30 mg / kg PO) caused anti-hyperalgesic actions in the rat carrageenan retention cushion model (test Hargreaves). The combinations in a fixed ratio (proportion 1 mg / gabapentin / 1 mg naproxen sodium or 1: 1) were anti-hyperalgesic and produced a significantly supra-additive effect (synergistic action). For example, with a dose ratio of 1: 1, dosages of naproxen sodium (0.05 mg / kg) plus gabapentin (0.05 mg / kg) that were less than 1/10. of the ED50 dose of the respective compounds alone, produced maximum anti-hyperalgesic effects when given in combination (see Table 1). The combinations in a fixed proportion (50 mg of gabapentin / 1 mg of naproxen sodium) were also anti-hyperalgesic, with a significant tendency towards a greater than that of the additive effect.

The data established that the combination of gabapentin and naproxen sodium is synergistic in its ability to relieve acute and chronic pain. The data also established that the most preferred combination of gabapentin plus naproxen sodium is in a combination of a fixed ratio close to 1: 1 (within some reasonable limit).

Table 1. Determined ED50 Values for Gabapentin, Naproxen and Two Fixed Rate Combinations in the Thermal Hyperalgesia Test in the Carrageenan Rat Retention Pad Drug for ED501 Treatment Gabapentin 17 mg / kg (2.4 - 46 mg / kg)? Naproxen sodium 0.36 mg / kg (0.007 - 1.26 mg / kg) t Theoretical 1: 1 (gabapentin: naproxen) 0.7 mg / kg combined total [0.35 mg / kg gabapentin plus 0.35 mg / kg naproxen] Experimental 1: 1 ( gabapentin: naproxen) 0.0022 mg / kg combined total (nd - 0.0020) t [0.00011 mg / kg gabapentin plus 0.00011 mg / kg naproxen] ** Theoretical 1: 1 (gabapenti naproxen) 9.0 mg / kg combined total [8.8 mg / kg of gabapentin plus 0.18 mg / kg of naproxen] Experimental 50: 1 (gabapentin: naproxen) 0.77 mg / kg combined total (0.06 -3.18 mg / kg) t [0.75 mg / kg of gabapentin plus 0.015 mg / kg of naproxen ] * t 95% of the confidence limits of the ED50 experimental values are shown in parentheses. * Significantly less than the theoretical additive ED50 combined, p < 0.05. ** Significantly less than the theoretical additive ED50 combined, p < 0.001. n.d. = not determined.

METHODS Animals Male Sprague-Dawley rats (200-250 g, Sasco Laboratories) were used. The rats were grouped into groups of 5 / cage in a light cycle: dark for 12 hours with free access to water and food. The rats received only one dose of a drug or a combination of drugs. All drugs were administered orally by a probe.

Experimental Design The first effect dose curves were determined for (1) gabapentin per se and (2) a prototypical NSAID (ie, naproxen) per se. The ED50 value and 95% of the confidence limits of each agent were determined, as was the time to represent effect. After administration in a proportion of the fixed dose with the NSAID; the drugs were administered in such a way that their effects were coincident. The ED50 values and 95% of the confidence limits were subsequently determined for the drugs in combination.

Measurements of Anti-noconception Thermal hyperalgesia induced carrageenan. The rats were acclimatized in a test chamber whose glass floor was maintained at 25 ° O Thirty minutes later, a flash of high intensity light was focused through the glass on the ventral surface of each hind paw and the latency of the reflex The removal of the paw from the flash of light was measured close to the second 0.1. This latency was conformed to the latency of the rapid leg movement (PFL). Two measurements of PCL spaced at 20 minutes were made for each leg and the second measurement was taken as the baseline of the response latency. After determination of the PFL baseline, 100 μL of 2% lambda-carrageenan was injected into the plantar surface of a hind paw and the animal was returned to the test chamber. Two hours later, when the thermal hyperalgesia was at maximum and stable, the vehicle was administered gabapentin, naproxen or gabapentin and naproxen by means of a tube. The response latencies for the contralateral and ipsilateral hind legs were subsequently re-determined 15, 30, 45, 60, 90 and 120 minutes later. The data for the subsequent analysis were taken 120 minutes after the oral dose.

Statistical Analysis The data were expressed as the mean ± SEM. Two variance analysis routes were used for repeated measurements to compare the effects of the drug to the vehicle. The dose-effect lines for gabapentin and the NSAID were constructed using individual data and arranged by linear least-squares regression analysis to determine the ED50 values and 95% accuracy limits. A similar analysis was conducted for the drugs in combination using the total dose administered. Since the parallel dose-effect lines were obtained for gabapentin, naproxen and the combination of gabapentin and naproxen, a parallel line test was subsequently conducted as described in Tallarida (Tallarida, 1992; Tallarida, et al; 1989 ). This analysis compared the position of the dose-effect line experimentally derived for the combination to the position of the theoretical dose-additive line. A significant deviation to the right or left of the theoretical dose-additive line indicates that the drugs interacted in a supra-additive (synergistic) or infra-additive (antagonist) manner, respectively. The preceding examples were presented so that the present invention is better understood and only for purposes of illustration and should not be considered as limiting the scope of the invention as defined by the following claims.

Claims (21)

1. A combination of an effective amount of at least one antiepileptic compound having pain relieving properties and an effective amount of at least one compound selected from the group consisting of NMDA receptor antagonists, NSAIDs, analgesics, and combinations thereof.

2. The combination according to claim 1, wherein the anti-epileptic compound is a compound of Formula I wherein R. is hydrogen or a lower alkyl, n is an integer from 4 to 6 and the cyclic ring is optionally substituted and the pharmaceutically acceptable salts thereof.

3. The combination according to claim 1, wherein the anti-epileptic compound is gabapentin.

4. The combination according to claim 1, wherein the anti-epileptic compound is a compound of Formula II R 1 wherein R n is a long or branched chain alkyl of 1 to 6 carbon atoms, phenyl or cycloalkyl having from 3 to 6 carbon atoms; R 2 is hydrogen or methyl and R 3 is hydrogen, methyl or carboxyl or an enantiomeric or diastereomeric isomer thereof or a pharmaceutically acceptable salt thereof.

5. The combination according to claim 1, wherein the anti-epileptic compound is pregabalin.

6. A combination of an effective amount of at least one anti-epileptic compound having pain relieving properties and an effective amount of an NMDA receptor antagonist.

7. The combination according to claim 6, wherein the anti-epileptic compound is gabapentin.

8. The combination according to claim 6, wherein the compound is pregabalin.

9. A combination of an effective amount of at least one anti-epileptic compound having pain relieving properties and an effective amount of an NSAID.

10. The combination according to claim 9, wherein the anti-epileptic compound is gabapentin.

11. The combination according to claim 9, wherein the anti-epileptic compound is pregabalin.

12. The combination according to claim 9, wherein the anti-epileptic compound is NSAID and naproxen.

13. A combination of an effective amount of at least one anti-epileptic compound having pain relief properties and an effective amount of a narcotic analgesic.

14. The combination according to claim 13, wherein the anti-epileptic compound is gabapentin.

15. The combination according to claim 13, wherein the anti-epileptic compound is pregabalin.

16. The combination of an effective amount of at least one anti-epileptic compound having pain relieving properties and an effective amount of two or more compounds selected from the group consisting of NMDA receptor antagonists, analgesics, NSAIDs and combinations thereof.

17. The combination according to claim 16, wherein two compounds are selected from the group consisting of NMDA receptor antagonists, analgesics, NSAIDs and combinations of the same.

18. The combination according to claim 17, wherein the two compounds are an analgesic and an NSAID.

19. The combination according to claim 18, wherein the two compounds are an opioid and an NSAID.

20. The combination according to claim 19, wherein the two compounds are morphine and naproxen.

21. The combination according to claim 16, wherein the anti-epileptic compound is gabapentin.